It is known that the morphine-like analgetics (opiates) act as respiratory-depressants. On the course of acute toxicity investigations lethality of such compounds is attributed to this activity [Prog. Neurobiol.33(1984)1-16; 22(1984) 345].
Interpretation of relations between respiratory-depressant activity and opiate receptors is rather difficult. According to the present conceptions there are several receptors which might participate in mediating this effect. However the relative contribution of various receptor populations mediating this effect is not clear enough. Since evaluating the respiratory parameters is complicated, selectivity of the methods is questionable and because of the big differences amongst the species the difficulties are further increased. The difficulties and problems inherent in these methods partially explain the difference in receptor assignments in opioid-induced respiratory depression which have appeared in literature.
Several biochemical and pharmacological data prove the heterogeneity of the opioid receptors both in the neurological system and in the periferies [Trends. Neuro. Sci.7.(1984) 31; Pharmac. Rev.39, 197-249 (1987).]
The main receptors--marked .mu., .delta., . and .sigma. receptors--show different dispersity in the different tissues, have different ligand specifities and mediate different physiological processes. In recent times it was clarified also that these main receptor types can be divided into sub-types. From these in the case of the .mu. type receptor it is possible to distinguish .mu..sub.1 and .mu..sub.2 sub-types. It is suggested that the .mu..sub.1 receptor mediates the analgesic effects of opiates while the .mu..sub.2 mediates opioid induced respiratory depression.
Identification of these two sub-types of opioid receptors may be brought about by way of their binding capacity to opioid receptors of so called high and low affinity. Ligands for .mu..sub.1 receptors are bound to the high affinity (.sup.3 H)naloxone binding sites. (Their affinity constants are below nanomole concentrations.) The .mu..sub.2 receptors (low affinity binding sites) mediates among others, opioid induced respiratory depression. (Their affinity constants are in the range of nanomole concentration or above.)
Ligands are known which are capable to inhibit selectively the .mu..sub.1 receptors. E.g. naloxonazine, oximorphazone, several other C-6 morphinane derivatives and interestingly also some peptides (the chloro-methyl-ketones of encephalones) are of this group.
As far as we are aware no compounds capable to block the .mu..sub.2 receptors were known hitherto. It is a new observation that codeinone, oxycodone and dihydrocodeinone derivatives substituted in position C-6 are bound in a partially irreversible manner to .mu..sub.2 receptors.
It has to be mentioned however that the existence of .mu..sub.1 and .mu..sub.2 receptors has not yet found general acceptance. There were several who could not repeat the experiment which serves as main proof namely that the respiratory depression caused by morphine is not inhibited by the selective .mu..sub.1 antagonist naloxonazine.
A further difficulty may be caused also by analysis of the complex action of opiates on respiration. There are opiates known which are depressing (.mu.-agonists: morphine etc.), others which are stimulating (receptor agonists: cyclazocine) and others which have dualistic (deprimating and stimulating) effects (partial antagonists: nalorphine).
The significance of identification of the .mu..sub.2 receptor would be in theory and in practice that knowing the same there would be a possibility to synthesize such compounds which would not have respiratory depressing while having considerable analgesic properties.
It is also known that there are certain dihydro-morphinone and dihydro-codeinone derivatives substituted in position 6 with hydrazone-, phenyl hydrazone, -dinitro-phenyl-hydrazone, semicarbazone and thiosemicarbazone groups as well as their 14-OH-derivatives possess increased analgesic activity as compared with the analogues which are 6-unsubstituted (Hungarian patent application No. 56-85 or patent specification 199.901).
The C-6 carbonyl group of the morphinane ketones is easily substituted and earlier publications suggest that changes of this type in general do not influence the opioide character of the ligand.
It has been stated when investigating 6-substituted hydrazone derivatives of 14-hydroxy- dihydro-morphinone [J.Med.Chem. 23 (1980) 674-677, Pharm.Res. 3 (1986) 56-60, Life Sci., 40 (1987) 1579-1588] that both the .mu. and the .delta. high affinity binding sites are irreversibly blocked by these derivatives [J.Pharm. Exp. Ther. (1980) 214 and 455-462 ]. It has been shown by pharmacological tests that, irreversible blocking of this receptor is manifested in the case of agonists in a long-lasting analgesic effect, while in the case of antagonists the analgetic activity of morphine is blocked for a long period of time while however the protection against lethal respiratory depression does not take place. [Life Sci. 31 (1983) 1389-1392, Science 208 (1989) 514-516]. It has thus been stated that the opiate analgesia is mediated by the common receptor named .mu..sub.1. Thus it would be a most desirable task for pharmaceutical planning to separate the analgetic effect from other opiate effects.